Target Discovery and Validation Reviews and Protocols

292 Sioud
Fig. 7. Bridging between innate and acquired immunity. After antigen capturing,
dendritic cells (DCs) migrate to draining lymph nodes. In the absence of danger signal
(e.g., inflammation or exogenous antigens), the DCs remain in an immature state that
present antigen to T-cells in the absence of co-stimulatory molecules (signal 2). This will
lead to either the deletion of T-cells or the generation of inducible regulatory T-cells (Tr1,
Th3). However, danger signals such tissue inflammations or viral or bacterial infections
induce the maturation of DCs and the migration of a large number of DCs to draining
lymph nodes. The expression of co-stimulatory molecules by DCs would lead to the
activation of T-cells, activation of B-cells via T-cell–secreted cytokines, and the generation
of effective adaptive immune response.
Despite the different central mechanisms operating on T- and B-positive selection,
it is hard to believe that all autoreactive cells are deleted. Many self-antigens
might not have access to the thymus, and others are only expressed later in
life. Thus, not all self-reactive cells are deleted in central organs. Low-affinity
self-reactive T-cells with specificity against antigens not represented in the primary
lymphoid tissues mature and join the peripheral lymphocyte pool. So,
there is a requirement for additional cellular and molecular mechanisms that
prevent these autoreactive cells in initiating an autoimmune disease. Several
mechanisms collectively referred to as “peripheral tolerance” normally operate
to prevent autoreactivity. These mechanisms include the induction of anergy